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Signal transduction for gene regulation
- Reptile freeze tolerance: Metabolism and gene expression

The implementation of adaptive metabolic responses to deal with the consequences of freezing requires efficient signaling mechanisms that translate environmental signals into metabolic and gene expression responses. For example, signals arising from β-adrenergic cell surface receptors trigger the cAMP-dependent protein kinase (PKA) in wood frog liver which in turn coordinates the activation of glycogenolysis and the production and export of glucose as the cryoprotectant [81]. The same system appears to act in C. picta liver [44]. The signaling mechanisms involved in freeze-responsive gene expression are still largely unconfirmed in freeze tolerant animals but multiple protein kinases have been implicated. For example, protein kinases C and G appear to mediate the up-regulation of the novel freeze-responsive proteins, FR47 and Li16, respectively, in freeze tolerant wood frogs [75]. Some other freeze responsive genes are known to be under the control of specific transcription factors such as the hypoxia-inducible factor (HIF-1) (see below) so that they may be regulated via well-established signal transduction pathways for mediating low oxygen signals in vertebrate systems. The mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that play a major role in the regulation of gene expression in cells responding to numerous growth factors, death signals, and environmental stresses [26]. Three MAPK modules are known: the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases or stress-activated kinases (JNK or SAPK), and the p38 kinases [26]. We analyzed responses to freezing and anoxia by the three MAPK modules in both wood frogs (R. sylvatica) and adult and hatchling turtles T. s. elegans [36], [37] and [38]. ERKs did not respond to freezing in wood frogs, to freezing or anoxia exposures in hatchling T. s. elegans, or to anoxia in adult turtles. JNK activities were not affected in wood frog organs over a 12 h freezing exposure but activities were reduced by 40–50% in turtle liver and heart over a 4 h freeze [36] and [38]. JNK activity rose during survivable anoxia exposure in tissues of both adult and hatchling turtles; activity peaked after 5 h of anoxic submergence in both cases but fell with longer exposure [36] and [37]. This suggests that JNKs may have a natural role to play in coordinating gene expression during the hypoxia transition period as animals prepare for full anaerobic function. However, a role for JNKs in freeze-responsive gene expression does not appear to occur although JNK activity had increased in wood frog organs after thawing which implies that it may act to aid recovery after freezing [38]. The active form of the p38 MAPK increased strongly in wood frog liver and kidney as an early response to freezing [38]. This kinase is well-known to mediate cell responses to a number of environmental stresses including osmotic stress [26] and, as such, is of great continuing interest to us as a potentially central signaling enzyme in freeze-responsive gene activation in freeze tolerant animals. It will be interesting to compare and contrast p38 responses to freeze/thaw and identify the genes up-regulated by p38 in freeze tolerant frogs and turtles to expand our understanding of the genes/proteins involved in natural freeze tolerance.

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